Histone deacetylases (HDAC) are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation.
HDAC inhibitors (HDACi) have effects on non-histone proteins that are related to acetylation. HDACi can alter the degree of acetylation of these molecules and, therefore, increase or repress their activity. HDACi have a long history of use in psychiatry and neurology as mood stabilizers and anti-epileptics, for example Valproic acid. In more recent times, they are being studied as antineoplastic and anti-inflammatory drugs.
In tumor cells, HDACi inhibit cell proliferation and induce cell death and differentiation [Gaofeng Bi and Guosheng Jiang in Cellular & Molecular Immunology 3, 285-290 (2006)].
Histone deacetylase inhibitors are also capable of modulating the production of cytokines and other pro-inflammatory factors on the part of immuno-competent cells and have demonstrated, in vivo, anti-inflammatory properties [Frederic Blanchard and Celine Chipoy in Drug Discovery Today 10, 197-204 (2005); IM Adcock in British Journal of Pharmacology 150, 829-831(2007)].
Some of the histone deacetylase inhibitors currently at the clinical study stage are described, with other analogues thereof, in the following patents: WO 2004/092115, WO 2005/019174, WO 2003/076422, WO 2006/010750, WO 2006/003068. WO 2002/030879, WO 2002/022577, WO 1993/007148, WO 2008/033747. WO 2004/069823, EP 0847992 and WO 2004/071400, the contents of which are incorporated herein by reference in their entirety.
Recently, a histone deacetylase inhibitor (Zolinza, Vorinostat) has been approved for the treatment of cutaneous T-cell lymphoma. Zolinza is in the form of capsule and is administered orally.
Givinostat (originally referred to as ITF2357) is described in WO 97/43251 (anhydrous form) and in WO 2004/065355 (monohydrate crystal form), herein both incorporated by reference. WO 2013/114413 describes the use of Givinostat for treating muscular dystrophy. Givinostat is an orally active histone deacetylase inhibitor.
In lipopolysaccharide (LPS)-stimulated cultured human peripheral blood mononuclear cells (PBMCs), ITF2357 reduces by 50% the release of tumor necrosis factor-α (TNFα) at concentration of 10 to 22 nM, the release of intracellular interleukin IL-1β at 12 nM, the secretion of IL-1β at 12.5 to 25 nM, and the production of interferon-γ (IFNγ) at 25 nM. Oral administration of 1.0 to 10 mg/kg ITF2357 to mice reduced LPS-induced serum TNFα and IFNγ by more than 50% [Flavio Leoni et al. in Molecular Medicine 11, 1-15 (2005)].
Givinostat is in numerous phase II clinical trials (including for relapsed leukemias and myelomas), and has been granted orphan drug designation in the European Union for the treatment of systemic juvenile idiopathic arthritis and polycythaemia vera and more recently for treatment of Duchenne muscular dystrophy. It is being used either alone or in combination with other drugs.
Solid dosage formulations are the commonest forms intended for oral administration of a drug. In spite of the numerous advantages they offer, many patients complain that it is difficult for them to take some currently used dosage forms such as tablets, capsules, or powders, due to difficulties in swallowing. This is particularly true for elderly and pediatric patients. In addition, patients on chemotherapy treatment may have nausea and emesis, which complicates the administration of conventional tablets and capsules.
WO 2004/092115, WO 2005/019174, and WO 2003/076422 describe histone deacetlase inhibitors that can be administered as pharmaceutical compositions by any of the following routes: oral, systemic (e.g., transdermal, intranasal or rectal), or parenteral administration, preferably administered by oral or parenteral route. However, in no cases, specific formulation aspects of oral suspension formulations are addressed, nor any manufacturing description of such formulations is given.
In particular, in the prior art, no specific formulation aspects of Givinostat oral suspension formulations are reported, nor any manufacturing description of such formulations is given.